9-substituted-8-oxo-adenine compounds as toll-like receptor (tlr7) modulators

ABSTRACT

The present invention provides compounds of formula 
     
       
         
         
             
             
         
       
     
     where n, R 1 , R 2 , A, X 1 , Y 1 , Z 1 , X 2  and Y 2  are as defined in the specification, processes for their preparation, pharmaceutical compositions containing them and their use in therapy.

The present invention relates to adenine derivatives, processes fortheir preparation, pharmaceutical compositions containing them and theiruse in therapy.

The immune system is comprised of innate and acquired immunity, both ofwhich work cooperatively to protect the host from microbial infections.It has been shown that innate immunity can recognize conservedpathogen-associated molecular patterns through toll-like receptors(TLRs) expressed on the cell surface of immune cells. Recognition ofinvading pathogens then triggers cytokine production (includinginterferon alpha(IFNα)) and upregulation of co-stimulatory molecules onphagocytes, leading to modulation of T cell function. Thus, innateimmunity is closely linked to acquired immunity and can influence thedevelopment and regulation of an acquired response.

TLRs are a family of type I transmembrane receptors characterized by anNH₂-terminal extracellular leucine-rich repeat domain (LRR) and aCOOH-terminal intracellular tail containing a conserved region calledthe Toll/IL-1 receptor (TIR) homology domain. The extracellular domaincontains a varying number of LRR, which are thought to be involved inligand binding. Eleven TLRs have been described to date in humans andmice. They differ from each other in ligand specificities, expressionpatterns, and in the target genes they can induce.

Ligands which act via TLRs (also known as immune response modifiers(IRMS)) have been developed, for example, the imidazoquinolinederivatives described in U.S. Pat. No. 4,689,338 which include theproduct Imiquimod for treating genital warts, and the adeninederivatives described in WO 98/01448 and WO 99/28321.

This patent application describes a class of 9-substituted-8-oxoadeninecompounds having immuno-modulating properties which act via TLR7 thatare useful in the treatment of viral or allergic diseases and cancers.

In accordance with the present invention, there is therefore provided acompound of formula

wherein

-   -   R¹ represents hydrogen, hydroxyl, or a C₁-C₆ alkoxy, C₂-C₅        alkoxycarbonyl, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, C₆-C₁₀ aryl,        C₅-C₁₀ heteroaryl or C₃-C₈ cycloalkyl group, each group being        optionally substituted by one or more substituents independently        selected from halogen, hydroxyl, C₁-C₆ alkyl, C₁-C₆ haloalkyl,        C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, C₂-C₅ alkoxycarbonyl, amino        (NH₂), (mono)-C₁-C₆ alkylamino and (di)-C₁-C₆ alkylamino;    -   Y¹ represents a single bond or C₁-C₆ alkylene;    -   X¹ represents a single bond, an oxygen or sulphur atom,        sulphonyl (SO₂) or NR³;    -   Z¹ represents a C₂-C₆ alkylene or C₃-C₈ cycloalkylene group,        each group being optionally substituted by at least one        hydroxyl;    -   X² represents NR⁴;    -   Y² represents a single bond or C₁-C₆ alkylene;    -   n is an integer 0, 1 or 2;    -   each R² group independently represents halogen, cyano,        S(O)_(m)R⁹, OR¹⁰, SO₂NR¹⁰R¹¹, CONR¹⁰R¹¹, NR¹⁰R¹¹, NR¹⁰SO₂R⁹,        NR¹⁰CO₂R⁹, NR¹⁰COR⁹, C₆-C₁₀ aryl, C₅-C₁₀ heteroaryl, C₁-C₆        alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl or C₃-C₈ cycloalkyl, the        latter six groups being optionally substituted by one or more        substituents independently selected from halogen, cyano,        S(O)_(p)R¹², OR¹³, SO₂NR¹³R¹⁴, CONR¹³R¹⁴, NR¹³R¹⁴, NR¹³SO₂R¹²,        NR¹³CO₂R¹², NR¹³COR¹², C₁-C₆ alkyl, C₁-C₃ haloalkyl and C₃-C₈        cycloalkyl;    -   R³ represents hydrogen or C₁-C₆ alkyl;    -   R⁴ represents CO₂R⁵, SO₂R⁵, COR⁵, SO₂NR⁶R⁷ or CONR⁶R⁷;    -   R⁵ represents        (i) a 3- to 8-membered saturated heterocyclic ring containing 1        or 2 ring heterogroups independently selected from NR⁸, S(O)_(q)        or oxygen, the ring being optionally substituted by one or more        substituents independently selected from halogen, hydroxyl,        C₁-C₆ alkyl and C₁-C₆ alkoxy, or        (ii) a C₆-C₁₀ aryl or C₅-C₁₀ heteroaryl group, each of which may        be optionally substituted by one or more substituents        independently selected from halogen, cyano, C₁-C₆ alkyl, C₁-C₃        haloalkyl, S(O)_(r)R⁹, OR¹⁰, CO₂R¹⁰, SO₂NR¹⁰R¹¹, CONR¹⁰R¹¹,        NR¹⁰R¹¹, NR¹⁰SO₂R⁹, NR¹⁰CO₂R⁹ and NR¹⁰COR⁹, or        (iii) a C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl or C₃-C₈        cycloalkyl group, each of which may be optionally substituted by        one or more substituents independently selected from halogen,        cyano, C₃-C₈ cycloalkyl, S(O)_(t)R¹², OR¹³, COR¹³, CO₂R¹³,        SO₂NR¹³R¹⁴, CONR¹³R¹⁴, NR⁶R⁷, NR¹³SO₂R¹², NR¹³CO₂R¹², NR¹³COR¹²,        C₆-C₁₀ aryl and C₅-C₁₀ heteroaryl, the latter two substituents        themselves being optionally substituted by one or more        substituents independently selected from C₁-C₆ alkyl, halogen,        hydroxy, methylsulphonyl and cyano;    -   R⁶ represents a hydrogen atom or a group selected from C₁-C₆        alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₈ cycloalkyl group and        a heterocyclic moiety, which group may be optionally substituted        by one or more substituents independently selected from halogen,        hydroxyl, oxo, cyano, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,        C₃-C₈ cycloalkyl, OR¹⁵, S(O)_(v)R¹⁵, CO₂R¹⁶, COR¹⁶, NR¹⁶R¹⁷,        CONR¹⁶R¹⁷, NR¹⁶COR¹⁷, NR¹⁶CO₂R¹⁵, SO₂NR¹⁶R¹⁷, NR¹⁶SO₂R¹⁵, C₆-C₁₀        aryl, C₅-C₁₀ heteroaryl and a heterocyclic moiety, the latter        three substituents themselves being optionally substituted by        one or more substituents independently selected from C₁-C₆        alkyl, C₃-C₈ cycloalkyl, halogen, S(O)_(w)R¹⁵, CO₂R¹⁶, COR¹⁶,        hydroxy and cyano, and    -   R⁷ represents a hydrogen atom or a C₁-C₆ alkyl, C₂-C₆ alkenyl,        C₂-C₆ alkynyl or C₃-C₈ cycloalkyl group, each group being        optionally substituted by one or more substituents independently        selected from halogen, C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, C₅-C₁₀        heteroaryl, carboxy, cyano, OR¹⁵, hydroxy and NR¹⁸R¹⁹, or    -   R⁶ and R⁷ together with the nitrogen atom to which they are        attached form a 3- to 8-membered saturated or partially        saturated heterocyclic ring optionally containing a further ring        heterogroup selected from nitrogen, S(O)_(x) and oxygen, the        heterocyclic ring being optionally substituted by one or more        substituents independently selected from halogen, hydroxyl,        carboxyl, cyano, OR²⁰, NR²¹R²², S(O)_(y)R²³, COR²⁴, CO₂R²⁴,        NR²⁴R²⁵, CONR²⁴R²⁵, NR²⁴COR²⁵, NR²⁴CO₂R²³, SO₂NR²⁴R²⁵,        NR²⁴SO₂R²³, C₆-C₁₀ aryl, benzyl, C₅-C₁₀ heteroaryl, a        heterocyclic moiety, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl        and C₃-C₈ cycloalkyl, the latter eight substituents themselves        being optionally substituted by one or more substituents        independently selected from halogen, oxo, cyano, OR²¹,        S(O)_(z)R²³, COR²⁴, COR²⁴ and NR²⁴R²⁵;    -   each R⁸, R¹⁰, R¹¹, R¹³, R¹⁴, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²¹, R²², R²⁴        and R²⁵ independently represents a hydrogen atom or a C₁-C₆        alkyl or C₃-C₆ cycloalkyl group;    -   each R⁹, R¹², R¹⁵ and R²³ independently represents C₁-C₆ alkyl        or C₃-C₆ cycloalkyl;    -   R²⁰ represents a C₁-C₆ alkyl group optionally substituted by one        or more substituents independently selected from halogen,        hydroxyl and OR²³;    -   m, p, q, r, t, v, w, x, y and z each independently represent an        integer 0, 1 or 2; and    -   A represents a C₆-C₁₀ aryl or C₅-C₁₂ heteroaryl group;        or a pharmaceutically acceptable salt thereof.

The compounds of the present invention are effective as TLR7 agonistsand may, additionally, possess properties such as low toxicity, goodselectivity and/or good metabolic stability which are advantageous forpharmaceutical compounds.

In the context of the present specification, unless otherwise stated, analkyl, alkenyl or alkynyl substituent group or an alkyl, alkenyl oralkynyl moiety in a substituent group may be linear or branched.Examples of C₁-C₆ alkyl groups/moieties include methyl, ethyl, propyl,2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl,3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl,2-methyl-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl,2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl,2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl,isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl and n-hexyl.Examples of C₂-C₆ alkenyl and C₂-C₆ alkynyl groups/moieties includeethenyl, propenyl, 1-butenyl, 2-butenyl, 1-pentenyl, 1-hexenyl,1,3-butadienyl, 1,3-pentadienyl, 1,4-pentadienyl, 1-hexadienyl, ethynyl,propynyl, 1-butynyl, 2-butynyl, 1-pentynyl and 1-hexynyl. Similarly, analkylene group/moiety may be linear or branched. Examples of C₁-C₆alkylene groups/moieties include methylene, ethylene, n-propylene,n-butylene, n-pentylene, n-hexylene, 1-methylethylene, 2-methylethylene,1,2-dimethylethylene, 1-ethylethylene, 2-ethylethylene, 1-, 2- or3-methylpropylene and 1-, 2- or 3-ethylpropylene. A C₁-C₆ haloalkyl orC₁-C₆ haloalkoxy substituent group/moiety will comprise at least onehalogen atom, e.g. one, two, three, four or five halogen atoms, examplesof which include trifluoromethyl, trifluoromethoxy or pentafluoroethyl.The alkyl groups in a di-C₁-C₆ alkylamino group/moiety may be the sameas, or different from, one another. A C₆-C₁₀ aryl or C₅-C₁₂ heteroarylsubstituent group/moiety may be monocyclic or polycyclic (e.g. bicyclicor tricyclic) in which the two or more rings are fused. The heteroarylsubstituent group/moiety will comprise at least one ring heteroatom(e.g. one, two, three or four ring heteroatoms independently) selectedfrom nitrogen, oxygen and sulphur. Examples of aryl and heteroarylgroups/moieties include phenyl, 1-naphthyl, 2-naphthyl, furyl, thienyl,pyrrolyl, pyridyl, indolyl, isoindolyl, quinolyl, isoquinolyl,pyrazolyl, imidazolyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiazolyland oxazolyl.

A heterocyclic moiety is defined as a saturated or partially saturated3- to 8-membered ring containing at least one ring heterogroup selectedfrom nitrogen, S(O)_(k) or oxygen (where k is 0, 1 or 2), which ring maybe fused with a C₆-C₁₀ aryl or C₅-C₁₂ heteroaryl group as defined above.Examples of heterocyclic moieties include morpholine, azetidine,pyrrolidine, piperidine, piperazine, 3-pyrroline, isoindoline,tetrahydroquinoline and thiomorpholine. For the avoidance of doubt, itshould be understood that the definitions of the heteroaryl groups andthe heterocyclic moieties in formula (I) are not intended to includeunstable structures or any O—O, O—S or S—S bonds and that a substituent,if present, may be attached to any suitable ring atom.

When any chemical moiety or group in formula (I) is described as beingoptionally substituted, it will be appreciated that the moiety or groupmay be either unsubstituted or substituted by one or more of thespecified substituents. It will be appreciated that the number andnature of substituents will be selected so as to avoid stericallyundesirable combinations.

In formula (I), R¹ represents hydrogen, hydroxyl, or a group selectedfrom

C₁-C₆, preferably C₁-C₄, alkoxy (e.g. methoxy, ethoxy, n-propoxy,isopropoxy, n-butoxy, isobutoxy, tert-butoxy, n-pentoxy or n-hexoxy),C₂-C₅ alkoxycarbonyl (e.g. ethoxycarbonyl, n-propoxycarbonyl,isopropoxycarbonyl, n-butoxycarbonyl, isobutoxycarbonyl,tert-butoxycarbonyl or n-pentoxycarbonyl),C₁-C₆, preferably C₁-C₄, haloalkyl (e.g. trifluoromethyl orpentafluoroethyl),C₁-C₆, preferably C₁-C₄, haloalkoxy (e.g. trifluoromethoxy),C₆-C₁₀, preferably C₆, aryl (e.g. phenyl, indenyl, naphthyl orazulenyl),C₅-C₁₀, preferably C₅-C₆, heteroaryl (e.g. pyridinyl, pyridazinyl,pyrazyl, triazinyl, indolyl, isoindolyl, quinolyl, isoquinolyl,pyrrolyl, pyrazolyl, imidazolyl, (1,2,3,)- and (1,2,4)-triazolyl,pyrazinyl, pyrimidinyl, tetrazolyl, furyl, thienyl, isoxazolyl,thiazolyl and oxazolyl)andC₃-C₈, preferably C₃-C₆, cycloalkyl (such as cyclopropyl, cyclobutyl,cyclopentyl or cyclohexyl),which group may be optionally substituted by one or more (e.g. one, two,three or four) substituents independently selected from halogen (e.g.chlorine, fluorine, bromine or iodine), hydroxyl, C₁-C₆, preferablyC₁-C₄, alkyl (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, tert-butyl, n-pentyl or n-hexyl), C₁-C₆, preferably C₁-C₄,haloalkyl (e.g. trifluoromethyl or pentafluoroethyl), C₁-C₆, preferablyC₁-C₄, alkoxy (e.g. methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy,isobutoxy, tert-butoxy, n-pentoxy or n-hexoxy),C₁-C₆, preferably C₁-C₄, haloalkoxy (e.g. trifluoromethoxy),C₂-C₅ alkoxycarbonyl (e.g. ethoxycarbonyl, n-propoxycarbonyl,isopropoxycarbonyl, n-butoxycarbonyl, isobutoxycarbonyl,tert-butoxycarbonyl or n-pentoxycarbonyl), amino, (mono)-C₁-C₆,preferably C alkylamino (e.g. methylamino, ethylamino, n-propylamino,isopropylamino, n-butylamino, isobutylamino, tert-butylamino,n-pentylamino or n-hexylamino) and (di)-C₁-C₆, preferably C₁-C₄,alkylamino (e.g. dimethylamino or diethylamino).

In an embodiment of the invention, R¹ represents hydrogen, hydroxyl, ora C₁-C₄ alkoxy, C₂-C₅ alkoxycarbonyl, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy,phenyl, C₅-C₆ heteroaryl or C₅-C₆ cycloalkyl group, each group beingoptionally substituted by one, two, three or four substituentsindependently selected from fluorine, chlorine, hydroxyl, C₁-C₄ alkyl,C₁-C₄ haloalkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkoxy, C₂-C₅ alkoxycarbonyl,amino, (mono)-C₁-C₄ alkylamino and (di)-C₁-C₄ alkylamino.

In another embodiment, R¹ represents hydrogen.

Y¹ represents a single bond or C₁-C₆, preferably C₁-C₄, alkylene (suchas methylene, ethylene, n-propylene, n-butylene, n-pentylene,n-hexylene, 1-methylethylene, 2-methylethylene, 1,2-dimethylethylene,1-ethylethylene, 2-ethylethylene, 1-, 2- or 3-methylpropylene or 1-, 2-or 3-ethylpropylene).

In an embodiment of the invention, Y¹ represents C₁-C₆ alkylene.

In another embodiment, Y¹ represents C₄ alkylene, particularlyn-butylene.

In an embodiment of the invention, X¹ represents oxygen.

In an embodiment of the invention, when X¹ represents oxygen, Y¹represents C₁-C₆ alkylene and R¹ represents hydrogen.

Z¹ represents a C₂-C₆, preferably C₂-C₄, alkylene (e.g. ethylene,n-propylene, n-butylene, n-pentylene, n-hexylene, 1-methylethylene,2-methylethylene, 1,2-dimethylethylene, 1-ethylethylene,2-ethylethylene, 1-, 2- or 3-methylpropylene or 1-, 2- or3-ethylpropylene) or C₃-C₈ cycloalkylene (e.g. cyclopropylene,cyclobutylene, cyclopentylene or cyclohexylene) group, each group beingoptionally substituted by at least one, e.g. one, two or three, hydroxylgroups.

In an embodiment of the invention, Z¹ represents C₂-C₆ alkylene,preferably C₃ alkylene (e.g. n-propylene).

X² represents NR⁴ where R⁴ represents CO₂R⁵, SO₂R⁵, COR⁵, SO₂NR⁶R⁷ orCONR⁶R⁷.

In an embodiment of the invention, R⁴ represents COR⁵.

Y² represents a single bond or C₁-C₆, preferably C₁-C₄, alkylene (suchas methylene, ethylene, n-propylene, n-butylene, n-pentylene,n-hexylene, 1-methylethylene, 2-methylethylene, 1,2-dimethylethylene,1-ethylethylene, 2-ethylethylene, 1-, 2- or 3-methylpropylene or 1-, 2-or 3-ethylpropylene).

In an embodiment of the invention, Y² represents C₁-C₆ alkylene,particularly methylene.

R⁵ represents

(i) a 3- to 8-, preferably 5- to 6-membered saturated heterocyclic ringcontaining 1 or 2 ring heterogroups independently selected from NR⁸,S(O)_(q) or oxygen, the ring being optionally substituted by one or more(e.g. one, two, three or four) substituents independently selected fromhalogen (e.g. fluorine, chlorine, bromine or iodine), hydroxyl, C₁-C₆,preferably C₁-C₄, alkyl (e.g. methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl) and C₁-C₆,preferably C alkoxy (e.g. methoxy, ethoxy, n-propoxy, isopropoxy,n-butoxy, isobutoxy, tert-butoxy, n-pentoxy or n-hexoxy), or(ii) a C₆-C₁₀, preferably C₆, aryl or C₅-C₁₀, preferably C₅-C₆,heteroaryl group (examples of aryl and heteroaryl groups being the sameas defined above for R¹), the aryl or heteroaryl group being optionallysubstituted by one or more (e.g. one, two, three or four) substituentsindependently selected from halogen (e.g. fluorine, chlorine, bromine oriodine), cyano, C₁-C₆, preferably C₁-C₄, alkyl (e.g. methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl orn-hexyl), C₁-C₃ haloalkyl (e.g. trifluoromethyl or pentafluoroethyl),S(O)_(r)R⁹, OR¹⁰, CO₂R¹⁰, SO₂NR¹⁰R¹¹, CONR¹⁰R¹¹, NR¹⁰R¹¹, NR¹⁰SO₂R⁹,NR¹⁰CO₂R⁹ and NR¹⁰COR⁹, or(iii) a group selected fromC₁-C₆, preferably C₁-C₄, alkyl (e.g. methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl),C₂-C₆, preferably C₂-C₄, alkenyl (e.g. ethenyl, propenyl, 1-butenyl,2-butenyl, 1-pentenyl, 1-hexenyl, 1,3-butadienyl, 1,3-pentadienyl,1,4-pentadienyl or 1-hexadienyl),C₂-C₆, preferably C₂-C₄, alkynyl (e.g. ethynyl, propynyl, 1-butynyl,2-butynyl, 1-pentynyl or 1-hexynyl) andC₃-C₈, preferably C₃-C₆, cycloalkyl (e.g. cyclopropyl, cyclobutyl,cyclopentyl or cyclohexyl),which group may be optionally substituted by one or more (e.g. one, two,three or four) substituents independently selected from halogen (e.g.fluorine, chlorine, bromine or iodine), cyano, C₃-C₈, preferably C₃-C₆,cycloalkyl (e.g. cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl),S(O)_(t)R¹², OR¹³, COR¹³, CO₂R¹³, SO₂NR¹³R¹⁴, CONR¹³R¹⁴, NR⁶R⁷,NR¹³SO₂R¹², NR¹³CO₂R¹², NR¹³COR¹², C₆-C₁₀, preferably C₆, aryl andC₅-C₁₀, preferably C₅-C₆, heteroaryl, the latter two substituentsthemselves being optionally substituted by one or more (e.g. one, two,three or four) substituents independently selected from C₁-C₆,preferably C₁-C₄, alkyl (e.g. methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl), halogen (e.g.fluorine, chlorine, bromine or iodine), hydroxy, methylsulphonyl andcyano.

In an embodiment of the invention, R⁵ represents a 5- to 6-memberedsaturated heterocyclic ring containing 1 or 2 ring heterogroupsindependently selected from NR⁸, S(O)_(q) or oxygen, the ring beingoptionally substituted by one, two, three or four substituentsindependently selected from fluorine, chlorine, hydroxyl, C₁-C₄ alkyland C₁-C₄ alkoxy.

In another embodiment, R⁵ represents phenyl or C₅-C₆ heteroaryl, each ofwhich may be optionally substituted by one, two, three or foursubstituents independently selected from fluorine, chlorine, cyano,C₁-C₄ alkyl, trifluoromethyl, S(O)_(r)R⁹, OR¹⁰, CO₂R¹⁰, SO₂NR¹⁰R¹¹,CONR¹⁰R¹¹, NR¹⁰R¹¹, NR¹⁰ SO₂R⁹, NR¹⁰CO₂R⁹ and NR¹⁰COR⁹.

In yet another embodiment, R⁵ represents a group selected from C₁-C₄alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl and C₃-C₆ cycloalkyl, which groupmay be optionally substituted by one, two, three or four substituentsindependently selected from fluorine, chlorine, cyano, C₃-C₆ cycloalkyl,S(O)_(t)R¹², OR¹³, COR¹³, CO₂R¹³, SO₂NR¹³R¹⁴, CONR¹³R¹⁴, NR⁶R⁷,NR¹³SO₂R¹², NR¹³CO₂R¹², NR¹³COR¹², phenyl and C₅-C₆ heteroaryl, thelatter two substituents themselves being optionally substituted by one,two, three or four substituents independently selected from C₁-C₄,alkyl, fluorine, chlorine, hydroxy, methylsulphonyl and cyano.

In a still further embodiment, R⁵ represents C₁-C₄ alkyl optionallysubstituted by one or two substituents independently selected fromfluorine, chlorine, cyano, C₃-C₆ cycloalkyl, S(O)_(t)R¹², OR¹³, COR¹³,CO₂R¹³, SO₂NR¹³R¹⁴, CONR¹³R¹⁴, NR⁶R⁷, NR¹³SO₂R¹², NR¹³CO₂R¹², NR¹³COR¹²,phenyl and C₅-C₆ heteroaryl, the latter two substituents themselvesbeing optionally substituted by one, two, three or four substituentsindependently selected from C₁-C₄ alkyl, fluorine, chlorine, hydroxy,methylsulphonyl and cyano.

In another embodiment, R⁵ represents C₁-C₄ alkyl optionally substitutedby one or two substituents independently selected from OR¹³, CO₂R¹³,CONR¹³R¹⁴, NR⁶R⁷, phenyl and C₅-C₆ heteroaryl, the latter twosubstituents themselves being optionally substituted by one, two, threeor four substituents independently selected from C₁-C₄ alkyl andmethylsulphonyl.

In a further embodiment, R⁵ represents C₁-C₄, preferably C₁-C₂, alkyloptionally substituted by one or two substituents independently selectedfrom OR¹³, CO₂R¹³, CONR¹³R¹⁴, NR⁶R⁷, phenyl and C₅-C₆ heteroaryl (e.g.triazolyl or pyrazinyl), the latter two substituents themselves beingoptionally substituted by one or two substituents independently selectedfrom C₁-C₄ alkyl (e.g. methyl) and methylsulphonyl.

In an embodiment of the invention, R⁶ represents a hydrogen atom or agroup selected from

C₁-C₆, preferably C₁-C₄, alkyl (e.g. methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl),C₂-C₆, preferably C₂-C₄, alkenyl (e.g. ethenyl, propenyl, 1-butenyl,2-butenyl, 1-pentenyl, 1-hexenyl, 1,3-butadienyl, 1,3-pentadienyl,1,4-pentadienyl or 1-hexadienyl),C₂-C₆, preferably C₂-C₄, alkynyl (e.g. ethynyl, propynyl, 1-butynyl,2-butynyl, 1-pentynyl or 1-hexynyl),C₃-C₈, preferably C₃-C₆, cycloalkyl (e.g. cyclopropyl, cyclobutyl,cyclopentyl or cyclohexyl), anda heterocyclic moiety,which group may be optionally substituted by one or more (e.g. one, two,three or four) substituents independently selected from halogen (e.g.fluorine, chlorine, bromine or iodine), hydroxyl, oxo, cyano, C₁-C₆,preferably C₁-C₄, alkyl, C₂-C₆, preferably C₂-C₄, alkenyl, C₂-C₆,preferably C₂-C₄, alkynyl, C₃-C₈, preferably C₃-C₆, cycloalkyl, OR¹⁵,S(O)_(v)R¹⁵, CO₂R¹⁶, COR¹⁶, NR¹⁶R¹⁷, CONR¹⁶R¹⁷, NR¹⁶COR¹⁷, NR¹⁶CO₂R¹⁵,SO₂NR¹⁶R¹⁷, NR¹⁶SO₂R¹⁵, C₆-C₁₀, preferably C₆, aryl, C₅-C₁₀, preferablyC₅-C₆, heteroaryl and a heterocyclic moiety, the latter threesubstituents themselves being optionally substituted by one or more(e.g. one, two, three or four) substituents independently selected fromC₁-C₆, preferably C₁-C₄, alkyl, C₃-C₈, preferably C₃-C₆, cycloalkyl,halogen (e.g. fluorine, chlorine, bromine or iodine), S(O)_(w)R¹⁵,CO₂R¹⁶, COR¹⁶, hydroxy and cyano; andR⁷ represents a hydrogen atom or a C₁-C₆, preferably C₁-C₄, alkyl (e.g.methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl,n-pentyl or n-hexyl),C₂-C₆, preferably C₂-C₄, alkenyl (e.g. ethenyl, propenyl, 1-butenyl,2-butenyl, 1-pentenyl, 1-hexenyl, 1,3-butadienyl, 1,3-pentadienyl,1,4-pentadienyl or 1-hexadienyl), C₂-C₆, preferably C₂-C₄, alkynyl (e.g.ethynyl, propynyl, 1-butynyl, 2-butynyl, 1-pentynyl or 1-hexynyl), orC₃-C₈, preferably C₃-C₆, cycloalkyl (e.g. cyclopropyl, cyclobutyl,cyclopentyl or cyclohexyl) group, each group being optionallysubstituted by one or more (e.g. one, two, three or four) substituentsindependently selected from halogen (e.g. fluorine, chlorine, bromine oriodine), C₃-C₈, preferably C₃-C₆, cycloalkyl, C₆-C₁₀, preferably C₆,aryl, C₅-C₁₀, preferably C₅-C₆, heteroaryl, carboxy, cyano, OR¹⁵,hydroxy and NR¹⁸R¹⁹.

In an embodiment of the invention, R⁶ and R⁷ each represent a C₁-C₆,preferably C₁-C₄, alkyl group, e.g. methyl.

In an alternative embodiment of the invention, R⁶ and R⁷ together withthe nitrogen atom to which they are attached form a 3- to 8-, preferably5- to 6-membered saturated or partially saturated heterocyclic ringoptionally containing a further ring heterogroup selected from nitrogen,S(O)_(x) and oxygen, the heterocyclic ring being optionally substitutedby one or more (e.g. one, two, three or four) substituents independentlyselected from halogen (e.g. fluorine, chlorine, bromine or iodine),hydroxyl, carboxyl, cyano, OR²⁰, NR²¹R²², S(O)_(y)R²³, COR²⁴, CO₂R²⁴,NR²⁴R²⁵, CONR²⁴R²⁵, NR²⁴COR²⁵, NR²⁴CO₂R²³, SO₂NR²⁴R²⁵, NR²⁴SO₂R²³,C₆-C₁₀, preferably C₆, aryl, benzyl, C₅-C₁₀, preferably C₅-C₆,heteroaryl, a heterocyclic moiety, C₁-C₆, preferably C₁-C₄, alkyl,C₂-C₆, preferably C₂-C₄, alkenyl, C₂-C₆, preferably C₂-C₄, alkynyl andC₃-C₈, preferably C₃-C₆, cycloalkyl, the latter eight substituentsthemselves being optionally substituted by one or more (e.g. one, two,three or four) substituents independently selected from halogen (e.g.fluorine, chlorine, bromine or iodine), oxo, cyano, OR²¹, S(O)_(z)R²³,COR²⁴, CO₂R²⁴ and NR²⁴R²⁵.

In an embodiment of the invention, R⁶ and R⁷ together with the nitrogenatom to which they are attached form a 5- to 6-membered saturatedheterocyclic ring optionally containing a further ring heterogroupselected from nitrogen, S(O)_(x) and oxygen, the heterocyclic ring beingoptionally substituted as defined above.

In another embodiment, R⁶ and R⁷ together with the nitrogen atom towhich they are attached form a piperazinyl ring substituted by benzyl.

Each group R⁸, R¹⁰, R¹¹, R¹³, R¹⁴, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²¹, R²², R²⁴ andR²⁵ independently represents a hydrogen atom or a C₁-C₆, preferablyC₁-C₄, alkyl (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, tert-butyl, n-pentyl or n-hexyl) or C₃-C₆, preferably C₅-C₆,cycloalkyl (i.e. cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl)group.

In an embodiment of the invention, each group R⁸, R¹⁰, R¹¹, R¹³, R¹⁴,R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²¹, R²², R²⁴ and R²⁵ independently represents ahydrogen atom or a C₁-C₆, preferably C₁-C₄, alkyl group.

In another embodiment, each group R⁸, R¹⁰, R¹¹, R¹³, R¹⁴, R¹⁶, R¹⁷, R¹⁸,R¹⁹, R²¹, R²², R²⁴ and R²⁵ independently represents a C₁-C₄ alkyl group,particularly a methyl group.

Each group R⁹, R¹², R¹⁵ and R²³ independently represents C₁-C₆,preferably C₁-C₄, alkyl (e.g. methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl) or C₃-C₆, preferablyC₅-C₆, cycloalkyl (i.e. cyclopropyl, cyclobutyl, cyclopentyl orcyclohexyl).

In an embodiment of the invention, each group R⁹, R¹², R¹⁵ and R²³independently represents a C₁-C₄ alkyl group, particularly a methylgroup.

R²⁰ represents a C₁-C₆, preferably C₁-C₄, alkyl group (e.g. methyl,ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl orn-hexyl) optionally substituted by one or more (e.g. one, two, three orfour) substituents independently selected from halogen (e.g. fluorine,chlorine, bromine or iodine), hydroxyl and OR²³.

A represents a C₆-C₁₀ aryl or C₅-C₁₂, preferably C₅-C₆, heteroarylgroup.

In an embodiment of the invention, A represents a C₆-C₁₀ aryl group,e.g. phenyl.

In formula (I), n is an integer 0, 1 or 2.

When n is 1 or 2, each R² group independently represents halogen (e.g.fluorine, chlorine, bromine or iodine), cyano, S(O)_(m)R⁹, OR¹⁰,SO₂NR¹⁰R¹¹, CONR¹⁰R¹¹, NR¹⁰R¹¹, NR¹⁰SO₂R⁹, NR¹⁰CO₂R⁹, NR¹⁰COR⁹, C₆-C₁₀,preferably C₆, aryl, C₅-C₁₀, preferably C₅-C₆, heteroaryl, C₁-C₆,preferably C₁-C₄, alkyl, C₂-C₆, preferably C₂-C₄, alkenyl, C₂-C₆,preferably C₂-C₄, alkynyl or C₃-C₈, preferably C₃-C₆, cycloalkyl, thelatter six groups being optionally substituted by one or more (e.g. one,two, three or four) substituents independently selected from halogen(e.g. fluorine, chlorine, bromine or iodine), cyano, S(O)_(p)R¹², OR¹³,SO₂NR¹³R¹⁴, CONR¹³R¹⁴, NR¹³R¹⁴, NR¹³SO₂R¹², NR¹³CO₂R¹², NR¹³COR¹²,C₁-C₆, preferably C₁-C₄, alkyl, C₁-C₃ haloalkyl and C₃-C₈, preferablyC₃-C₆, cycloalkyl.

In an embodiment of the invention, n is 0.

In an embodiment of the invention,

-   -   R¹ represents hydrogen;    -   Y¹ represents C₄ alkylene;    -   X¹ represents an oxygen atom;    -   Z¹ represents C₃ alkylene;    -   X² represents NR⁴;    -   Y² represents methylene;    -   n is 0;    -   R⁴ represents COR⁵;    -   R⁵ represents C₁-C₂ alkyl optionally substituted by one or two        substituents independently selected from OR¹³, CO₂R¹³,        CONR¹³R¹⁴, NR⁶R⁷, phenyl and C₅-C₆ heteroaryl, the latter two        substituents themselves being optionally substituted by one or        two substituents to independently selected from C₁-C₄ alkyl and        methylsulphonyl;    -   either R⁶ and R⁷ both represent C₁-C₄ alkyl, or R⁶ and R⁷        together with the nitrogen atom to which they are attached form        a piperazinyl ring substituted by benzyl;    -   each R¹³ and R¹⁴ independently represents C₁-C₄ alkyl; and    -   A represents C₆-C₁₀ aryl.

Examples of compounds of the invention include:

-   N-[3-(6-Amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl]-N-benzylacetamide,-   N-[3-(6-Amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl]-N-benzyl-2-methoxyacetamide,-   Methyl    4-[[3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl](benzyl)amino]-4-oxobutanoate,-   N-[3-(6-Amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl]-N-benzyl-3-methoxypropanamide,-   N-[3-(6-Amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl]-N-benzyl-N′,N′-dimethylsuccinamide,-   N-[3-(6-Amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl]-N-benzyl-2-[4-(methylsulfonyl)phenyl]acetamide,-   N-[3-(6-Amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl]-N-benzyl-2-(4-benzylpiperazin-1-yl)acetamide,-   N-[3-(6-Amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl]-N-benzyl-2-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)acetamide,-   N-[3-(6-Amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl]-N-benzyl-3-pyrazin-2-ylpropanamide,    and-   N-[3-(6-Amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl]-N-benzyl-N³,N³-dimethyl-β-alaninamide,    and their pharmaceutically acceptable salts.

It should be noted that each of the chemical compounds listed aboverepresents a particular and independent aspect of the invention.

The present invention further provides a process for the preparation ofa compound of formula (I) or a pharmaceutically acceptable salt thereofas defined above which comprises,

(a) when R⁴ represents a group COR⁵, reacting a compound of formula

wherein n, R¹, R², A, X¹, Y¹, Z¹ and Y² are as defined in formula (I),with a compound of formula (III), R¹⁵—C(O)-L¹, wherein L¹ representshalogen or hydroxy and R⁵ is as defined in formula (I), in the presenceof a base or a coupling reagent as required;(b) when R⁴ represents a group COR⁵ and R⁵ represents a group C₁-C₆alkyl-NR⁶R⁷, reacting a compound of formula

wherein R³⁰ represents a C₁-C₆ alkyl group, L² represents a leavinggroup (e.g. halogen, mesylate or triflate) and n, R¹, R², A, X¹, Y¹, Z¹and Y² are as defined in formula (I), with a compound of formula (V),NHR⁶R⁷, wherein R⁶ and R⁷ are as defined in formula (I), in the presenceof a base;(c) when R⁴ represents a group SO₂R⁵, reacting a compound of formula(II) as defined in (a) above with a compound of formula (VI),L³-S(O)₂—R⁵, wherein L³ represents a leaving group (e.g. halogen) and R⁵is as defined in formula (I), in the presence of a base;(d) when R⁴ represents a group CO₂R⁵, reacting a compound of formula(II) as defined in (a) above with a compound of formula (VII),L⁴-C(O)—OR⁵, wherein L⁴ represents a leaving group (e.g. halogen) and R⁵is as defined in formula (I), in the presence of a base;(e) when R⁴ represents a group SO₂NR⁶R⁷, reacting a compound of formula(II) as defined in (a) above with a compound of formula (VIII),L⁵-S(O)₂—NR⁶R⁷, wherein L⁵ represents a leaving group (e.g. halogen) andR⁶ and R⁷ are as defined in formula (I), in the presence of a base;or(f) when R⁴ represents a group CONR⁶R⁷, reacting a compound of formula(II) as defined in (a) above with a compound of formula (IX),L⁶-C(O)—NR⁶R⁷, wherein L⁶ represents a leaving group (e.g. halogen) andR⁶ and R⁷ are as defined in formula (I), in the presence of a base;and optionally thereafter carrying out one or more of the followingprocedures:

-   -   converting a compound of formula (I) into another compound of        formula (I),    -   removing any protecting groups,    -   forming a pharmaceutically acceptable salt.

In process (a) above, the reaction is conveniently carried out in anorganic solvent such as dimethylformamide, dichloromethane, acetonitrileor N-methylpyrrolidone at a temperature in the range from 0° C. to 150°C. If L¹ in formula (III) represents a halogen atom, the reaction iscarried out in the presence of a suitable base, examples of whichinclude diisopropyl ethylamine, triethylamine and pyridine. If L¹ informula (III) is hydroxy, then the reaction is carried out in thepresence of a coupling reagent, suitable examples of which includebenzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate(PyBop), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (EDC) andO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU).

In process (b) above, the reaction is conveniently carried out in anorganic solvent such as dimethylformamide, dimethylsulphoxide oracetonitrile at a temperature in the range from 0° C. to 150° C.Suitable bases include diisopropyl ethylamine, triethylamine andpyridine.

In each of processes (c), (d), (e) and (f) above, the reaction isconveniently carried out in an organic solvent such asdimethylformamide, dichloromethane or acetonitrile at a temperature inthe range from 0° C. to 150° C. Suitable bases include diisopropylethylamine, triethylamine and pyridine.

Compounds of formula (II) may be prepared by treating a compound offormula

wherein n, R¹, R², A, X¹, Y¹, Z¹ and Y² are as defined in formula (II)with an acid. The reaction may be carried out in an organic solvent suchas methanol, tetrahydrofuran or dioxane using either an inorganic acidsuch as hydrochloric acid, hydrobromic acid or sulfuric acid, or anorganic acid such as trifluoroacetic acid.

Compounds of formula (X) in which Y² represents C₁-C₆ alkylene may beprepared by reacting a compound of formula

wherein R¹, X¹, Y¹ and Z¹ are as defined in formula (X), with a compoundof formula

wherein Y³ represents a bond or a C₁-C₅ alkylene group and n, A and R²are as defined in formula (X). The reaction may be carried out in thepresence of a suitable reducing agent (for example, sodiumtriacetoxyborohydride or sodium borohydride), in an organic solvent suchas 1-methyl-2-pyrrolidinone, 1,2-dichloroethane, tetrahydrofuran ormethanol at a temperature, for example, in the range from 0° C. to 150°C.

Compounds of formula (X) in which Y² represents a single bond may beprepared by reacting a compound of formula (XI) as defined above with acompound of formula

wherein L⁷ represents a leaving group such as halogen or mesylate and n,A and R² are as defined in formula (X), in the presence of a base. Thereaction may be carried out in an organic solvent such asdimethylformamide, dioxane or acetonitrile at a temperature, forexample, in the range from 25° C. to 150° C. Suitable bases includediisopropyl ethylamine, triethylamine and potassium carbonate.

Compounds of formula (XI) may be prepared by treating a compound offormula

wherein PG₁ represents a protecting group (e.g. phthalimide or Fmoc) andR¹, X¹, Y¹ and Z¹ are as defined in formula (XI) with hydrazine inethanol or with an organic base such as piperidine.

Compounds of formula (XIV) may be prepared by reacting a compound offormula

wherein R¹, X¹ and Y¹ are as defined in formula (XIV) with a compound offormula (XVI), L⁸-Z¹—NH—PG₁, wherein L⁸ represents a leaving group (e.g.halogen, mesylate or triflate), and Z¹ and PG₁ are as defined in formula(XIV). The reaction may conveniently be carried out in an organicsolvent such as dimethylformamide, dimethylsulphoxide or acetonitrile inthe presense of a base such as an alkali metal carbonate (for example,sodium carbonate or potassium carbonate) or an alkaline earth metalcarbonate (for example, calcium carbonate) or a metal hydroxide (forexample, sodium hydroxide or potassium hydroxide), at a temperature, forexample, in the range from 0° C. to 150° C., preferably at roomtemperature (20° C.).

Compounds of formula (XV) where X¹ represents an oxygen atom may beprepared as illustrated in the following reaction scheme:

The compound of formula (B) is prepared by reacting the compound offormula (A) with ammonia in an organic solvent such as methanol,ethanol, propanol, butanol, tetrahydrofuran, 1,4-dioxane, diglyme,acetonitrile or an aqueous mixture of any one of the preceding solvents.The reaction may be carried out in an autoclave and at a temperature,for example, in the range from 20° C. to 200° C.

Compounds of formula (C) may be prepared by reacting the compound offormula (B) with an alcohol of formula

wherein R¹ and Y¹ are as defined in formula (XV), in the presence of abase such as sodium hydride and in an organic solvent such astetrahydrofuran, 1,4-dioxane, diglyme, N,N-dimethylformamide ordimethylsulfoxide, preferably at elevated temperature, e.g. at atemperature in the range from 20° C. to 150° C. Alternatively an alkalimetal such as sodium may be dissolved in a C₁-C₆ alkanol and thenreacted with the compound of formula (B), preferably at elevatedtemperature, e.g. at a temperature in the range from 20° C. to 150° C.

Compounds of formula (D) may be prepared by brominating a compound offormula (C). The reaction may be carried out using a brominating agentsuch as bromine, hydroperbromic acid or N-bromosuccinimide, in anorganic solvent such as carbon tetrachloride, methylene chloride,dichloroethane, diethyl ether, acetic acid or carbon disulfide. Thereaction temperature will generally be in the range from 0° C. to theboiling point of the solvent.

Compounds of formula (E) are prepared by reacting a compound of formula(D) with sodium methoxide in an organic solvent such as methanol and ata temperature, for example, in the range from 20° C. to 150° C.

Compounds of formula (F) may be obtained by treating a compound offormula (E) with an acid such as trifluoroacetic acid in an organicsolvent such as methanol.

Other compounds of formula (XV) may be prepared by processes known inthe art.

Compounds of formula (IV) may be prepared by reacting a compound offormula (II) with a compound of formula (XVIII), HO—C(O)—R³⁰-L², whereinR³⁰ and L² are as defined in formula (IV) under similar reactionconditions to those used in process (a) above.

Compounds of formulae (III), (V), (VI), (VII), (VIII), (IX), (XII),(XIII), (XVI), (XVII) and (XVIII) are either commercially available, arewell known in the literature or may be prepared easily using knowntechniques.

It will be appreciated by those skilled in the art that in the processesof the present invention certain functional groups such as hydroxyl oramino groups in the reagents may need to be protected by protectinggroups. Thus, the preparation of the compounds of formula (I) mayinvolve, at an appropriate stage, the removal of one or more protectinggroups.

The protection and deprotection of functional groups is described in‘Protective Groups in Organic Chemistry’, edited by J. W. F. McOmie,Plenum Press (1973) and ‘Protective Groups in Organic Synthesis’, 3^(rd)edition, T. W. Greene and P. G. M. Wuts, Wiley-Interscience (1999).

The compounds of formula (I) above may be converted to apharmaceutically acceptable salt thereof, preferably an acid additionsalt such as a hydrochloride, hydrobromide, trifluoroacetate, sulphate,phosphate, acetate, fumarate, maleate, tartrate, lactate, citrate,pyruvate, succinate, oxalate, methanesulphonate or p-toluenesulphonate.

Compounds of formula (I) are capable of existing in stereoisomericforms. It will be understood that the invention encompasses the use ofall geometric and optical isomers (including atropisomers) of thecompounds of formula (I) and mixtures thereof including racemates. Theuse of tautomers and mixtures thereof also form an aspect of the presentinvention. Enantiomerically pure forms are particularly desired.

The compounds of formula (I) and their pharmaceutically acceptable saltshave activity as pharmaceuticals, in particular as modulators oftoll-like receptor (especially TLR7) activity, and thus may be used inthe treatment of:

1. respiratory tract: obstructive diseases of the airways including:asthma, including bronchial, allergic, intrinsic, extrinsic,exercise-induced, drug-induced (including aspirin and NSAID-induced) anddust-induced asthma, both intermittent and persistent and of allseverities, and other causes of airway hyper-responsiveness; chronicobstructive pulmonary disease (COPD); bronchitis, including infectiousand eosinophilic bronchitis; emphysema; bronchiectasis; cystic fibrosis;sarcoidosis; farmer's lung and related diseases; hypersensitivitypneumonitis; lung fibrosis, including cryptogenic fibrosing alveolitis,idiopathic interstitial pneumonias, fibrosis complicatinganti-neoplastic therapy and chronic infection, including tuberculosisand aspergillosis and other fungal infections; complications of lungtransplantation; vasculitic and thrombotic disorders of the lungvasculature, and pulmonary hypertension; antitussive activity includingtreatment of chronic cough associated with inflammatory and secretoryconditions of the airways, and iatrogenic cough; acute and chronicrhinitis including rhinitis medicamentosa, and vasomotor rhinitis;perennial and seasonal allergic rhinitis including rhinitis nervosa (hayfever); nasal polyposis; acute viral infection including the commoncold, and infection due to respiratory syncytial virus, influenza,coronavirus (including SARS) and adenovirus;2. skin: psoriasis, atopic dermatitis, contact dermatitis or othereczematous dermatoses, and to delayed-type hypersensitivity reactions;phyto- and photodermatitis; seborrhoeic dermatitis, dermatitisherpetiformis, lichen planus, lichen sclerosus et atrophica, pyodermagangrenosum, skin sarcoid, discoid lupus erythematosus, pemphigus,pemphigoid, epidermolysis bullosa, urticaria, angioedema, vasculitides,toxic erythemas, cutaneous eosinophilias, alopecia areata, male-patternbaldness, Sweet's syndrome, Weber-Christian syndrome, erythemamultiforme; cellulitis, both infective and non-infective; panniculitis;cutaneous lymphomas, non-melanoma skin cancer and other dysplasticlesions; drug-induced disorders including fixed drug eruptions;3. eyes: blepharitis; conjunctivitis, including perennial and vernalallergic conjunctivitis; iritis; anterior and posterior uveitis;choroiditis; autoimmune, degenerative or inflammatory disordersaffecting the retina; ophthalmitis including sympathetic ophthalmitis;sarcoidosis; infections including viral, fungal, and bacterial;4. genitourinary: nephritis including interstitial andglomerulonephritis; nephrotic syndrome; cystitis including acute andchronic (interstitial) cystitis and Hunner's ulcer; acute and chronicurethritis, prostatitis, epididymitis, oophoritis and salpingitis;vulvo-vaginitis; Peyronie's disease; erectile dysfunction (both male andfemale);5. allograft rejection: acute and chronic following, for example,transplantation of kidney, heart, liver, lung, bone marrow, skin orcornea or following blood transfusion; or chronic graft versus hostdisease;6. other auto-immune and allergic disorders including rheumatoidarthritis, irritable bowel syndrome, systemic lupus erythematosus,multiple sclerosis, Hashimoto's thyroiditis, Graves' disease, Addison'sdisease, diabetes mellitus, idiopathic thrombocytopaenic purpura,eosinophilic fasciitis, hyper-IgE syndrome, antiphospholipid syndromeand Sazary syndrome;7. oncology: treatment of common cancers including prostate, breast,lung, ovarian, pancreatic, bowel and colon, stomach, skin and braintumors and malignancies affecting the bone marrow (including theleukaemias) and lymphoproliferative systems, such as Hodgkin's andnon-Hodgkin's lymphoma; including the prevention and treatment ofmetastatic disease and tumour recurrences, and paraneoplastic syndromes;and,8. infectious diseases: virus diseases such as genital warts, commonwarts, plantar warts, hepatitis B, hepatitis C, herpes simplex virus,molluscum contagiosum, variola, human immunodeficiency virus (HIV),human papilloma virus (HPV), cytomegalovirus (CMV), varicella zostervirus (VZV), rhinovirus, adenovirus, coronavirus, influenza,para-influenza; bacterial diseases such as tuberculosis andmycobacterium avium, leprosy; other infectious diseases, such as fungaldiseases, chlamydia, candida, aspergillus, cryptococcal meningitis,pneumocystis carnii, cryptosporidiosis, histoplasmosis, toxoplasmosis,trypanosome infection and leishmaniasis.

Thus, the present invention provides a compound of formula (I) or apharmaceutically-acceptable salt thereof as hereinbefore defined for usein therapy.

In a further aspect, the present invention provides the use of acompound of formula (I) or a pharmaceutically acceptable salt thereof ashereinbefore defined in the manufacture of a medicament for use intherapy.

In the context of the present specification, the term “therapy” alsoincludes “prophylaxis” unless there are specific indications to thecontrary. The terms “therapeutic” and “therapeutically” should beconstrued accordingly.

Prophylaxis is expected to be particularly relevant to the treatment ofpersons who have suffered a previous episode of, or are otherwiseconsidered to be at increased risk of, the disease or condition inquestion. Persons at risk of developing a particular disease orcondition generally include those having a family history of the diseaseor condition, or those who have been identified by genetic testing orscreening to be particularly susceptible to developing the disease orcondition.

In particular, the compounds of the invention (includingpharmaceutically acceptable salts) may be used in the treatment ofasthma, COPD, allergic rhinitis, allergic conjunctivitis, atopicdermatitis, cancer, hepatitis B, hepatitis C, HIV, HPV, bacterialinfections and dermatosis.

The invention still further provides a method of treating, or reducingthe risk of, a disease or condition comprising or arising from abnormalcell growth (e.g. a cancer), which method comprises administering to apatient in need thereof a therapeutically effective amount of a compoundof formula (I) or a pharmaceutically acceptable salt thereof ashereinbefore defined.

The invention also provides a method of treating, or reducing the riskof, an obstructive airways disease or condition (e.g. asthma or COPD)which comprises administering to a patient in need thereof atherapeutically effective amount of a compound of formula (I) or apharmaceutically acceptable salt thereof as hereinbefore defined.

For the above-mentioned therapeutic uses the dosage administered will,of course, vary with the compound employed, the mode of administration,the treatment desired and the disorder indicated. For example, the dailydosage of the compound of the invention, if inhaled, may be in the rangefrom 0.05 micrograms per kilogram body weight (μg/kg) to 100 microgramsper kilogram body weight (μg/kg). Alternatively, if the compound isadministered orally, then the daily dosage of the compound of theinvention may be in the range from 0.01 micrograms per kilogram bodyweight (μg/kg) to 100 milligrams per kilogram body weight (mg/kg).

The compounds of formula (I) and pharmaceutically acceptable saltsthereof may be used on their own but will generally be administered inthe form of a pharmaceutical composition in which the formula (I)compound/salt (active ingredient) is in association with apharmaceutically acceptable adjuvant, diluent or carrier. Conventionalprocedures for the selection and preparation of suitable pharmaceuticalformulations are described in, for example, “Pharmaceuticals—The Scienceof Dosage Form Designs”, M. E. Aulton, Churchill Livingstone, 1988.

Depending on the mode of administration, the pharmaceutical compositionwill preferably comprise from 0.05 to 99% w (percent by weight), morepreferably from 0.05 to 80% w, still more preferably from 0.10 to 70% w,and even more preferably from 0.10 to 50% w, of active ingredient, allpercentages by weight being based on total composition.

The present invention also provides a pharmaceutical compositioncomprising a compound of formula (I) or a pharmaceutically acceptablesalt thereof as hereinbefore defined, in association with apharmaceutically acceptable adjuvant, diluent or carrier.

The invention further provides a process for the preparation of apharmaceutical composition of the invention which comprises mixing acompound of formula (I) or a pharmaceutically acceptable salt thereof ashereinbefore defined with a pharmaceutically acceptable adjuvant,diluent or carrier.

The pharmaceutical compositions may be administered topically (e.g. tothe skin or to the lung and/or airways) in the form, e.g., of creams,solutions, suspensions, heptafluoroalkane (HFA) aerosols and dry powderformulations, for example, formulations in the inhaler device known asthe Turbuhaler®; or systemically, e.g. by oral administration in theform of tablets, capsules, syrups, powders or granules; or by parenteraladministration in the form of a sterile solution, suspension or emulsionfor injection (including intravenous, subcutaneous, intramuscular,intravascular or infusion); or by rectal administration in the form ofsuppositories.

Dry powder formulations and pressurized HFA aerosols of the compounds ofthe invention (including pharmaceutically acceptable salts) may beadministered by oral or nasal inhalation. For inhalation, the compoundis desirably finely divided. The finely divided compound preferably hasa mass median diameter of less than 10 micrometres (μm), and may besuspended in a propellant mixture with the assistance of a dispersant,such as a C₈-C₂₀ fatty acid or salt thereof, (for example, oleic acid),a bile salt, a phospholipid, an alkyl saccharide, a perfluorinated orpolyethoxylated surfactant, or other pharmaceutically acceptabledispersant. The compounds of the invention may also be administered bymeans of a dry powder inhaler. The inhaler may be a single or a multidose inhaler, and may be a breath actuated dry powder inhaler.

One possibility is to mix the finely divided compound of the inventionwith a carrier substance, for example, a mono-, di- or polysaccharide, asugar alcohol, or another polyol. Suitable carriers are sugars, forexample, lactose, glucose, raffinose, melezitose, lactitol, maltitol,trehalose, sucrose, mannitol; and starch. Alternatively the finelydivided compound may be coated by another substance. The powder mixturemay also be dispensed into hard gelatine capsules, each containing thedesired dose of the active compound.

Another possibility is to process the finely divided powder into sphereswhich break up during the inhalation procedure. This spheronized powdermay be filled into the drug reservoir of a multidose inhaler, forexample, that known as the Turbuhaler® in which a dosing unit meters thedesired dose which is then inhaled by the patient. With this system theactive ingredient, with or without a carrier substance, is delivered tothe patient.

For oral administration the compound of the invention may be admixedwith an adjuvant or a carrier, for example, lactose, saccharose,sorbitol, mannitol; a starch, for example, potato starch, corn starch oramylopectin; a cellulose derivative; a binder, for example, gelatine orpolyvinylpyrrolidone; and/or a lubricant, for example, magnesiumstearate, calcium stearate, polyethylene glycol, a wax, paraffin, andthe like, and then compressed into tablets. If coated tablets arerequired, the cores, prepared as described above, may be coated with aconcentrated sugar solution which may contain, for example, gum arabic,gelatine, talcum and titanium dioxide. Alternatively, the tablet may becoated with a suitable polymer dissolved in a readily volatile organicsolvent.

For the preparation of soft gelatine capsules, the compound of theinvention may be admixed with, for example, a vegetable oil orpolyethylene glycol. Hard gelatine capsules may contain granules of thecompound using either the above-mentioned excipients for tablets. Alsoliquid or semisolid formulations of the compound of the invention may befilled into hard gelatine capsules.

Liquid preparations for oral application may be in the form of syrups orsuspensions, for example, solutions containing the compound of theinvention, the balance being sugar and a mixture of ethanol, water,glycerol and propylene glycol. Optionally such liquid preparations maycontain colouring agents, flavouring agents, saccharine and/orcarboxymethylcellulose as a thickening agent or other excipients knownto those skilled in art.

The compounds of the invention (that is, compounds of formula (I) andpharmaceutically acceptable salts thereof) may also be administered inconjunction with other compounds used for the treatment of the aboveconditions.

The invention therefore further relates to combination therapies whereina compound of the invention or a pharmaceutical composition orformulation comprising a compound of the invention is administeredconcurrently or sequentially or as a combined preparation with anothertherapeutic agent or agents, for the treatment of one or more of theconditions listed.

The anti-cancer treatment defined hereinbefore may be applied as a soletherapy or may involve, in addition to the compound of the invention,conventional surgery or radiotherapy or chemotherapy. Such chemotherapymay include one or more of the following categories of anti-tumouragents:—

(i) other antiproliferative/antineoplastic drugs and combinationsthereof, as used in medical oncology, such as alkylating agents (forexample cis-platin, oxaliplatin, carboplatin, cyclophosphamide, nitrogenmustard, melphalan, chlorambucil, busulphan, temozolamide andnitrosoureas); antimetabolites (for example gemcitabine and antifolatessuch as fluoropyrimidines like 5-fluorouracil and tegafur, raltitrexed,methotrexate, cytosine arabinoside, and hydroxyurea); antitumourantibiotics (for example anthracyclines like adriamycin, bleomycin,doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C,dactinomycin and mithramycin); antimitotic agents (for example vincaalkaloids like vincristine, vinblastine, vindesine and vinorelbine andtaxoids like taxol and taxotere and polokinase inhibitors); andtopoisomerase inhibitors (for example epipodophyllotoxins like etoposideand teniposide, amsacrine, topotecan and camptothecin);(ii) cytostatic agents such as antioestrogens (for example tamoxifen,fulvestrant, toremifene, raloxifene, droloxifene and iodoxyfene),antiandrogens (for example bicalutamide, flutamide, nilutamide andcyproterone acetate), LHRH antagonists or LHRH agonists (for examplegoserelin, leuprorelin and buserelin), progestogens (for examplemegestrol acetate), aromatase inhibitors (for example as anastrozole,letrozole, vorazole and exemestane) and inhibitors of 5α-reductase suchas finasteride;(iii) anti-invasion agents (for example c-Src kinase family inhibitorslike4-(6-chloro-2,3-methylenedioxyanilino)-7-[2-(4-methylpiperazin-1-yl)ethoxy]-5-tetrahydropyran-4-yloxyquinazoline(AZD0530; International Patent Application WO 01/94341) andN-(2-chloro-6-methylphenyl)-2-{6-[4-(2-hydroxyethyl)piperazin-1-yl]-2-methylpyrimidin-4-ylamino}thiazole-5-carboxamide(dasatinib, BMS-354825; J. Med. Chem., 2004, 47, 6658-6661), andmetalloproteinase inhibitors like marimastat, inhibitors of urokinaseplasminogen activator receptor function or antibodies to Heparanase);(iv) inhibitors of growth factor function: for example such inhibitorsinclude growth factor antibodies and growth factor receptor antibodies(for example the anti-erbB2 antibody trastuzumab [Herceptin™], theanti-EGFR antibody panitumumab, the anti-erbB1 antibody cetuximab[Erbitux, C225] and any growth factor or growth factor receptorantibodies disclosed by Stern et al. Critical reviews inoncology/haematology, 2005, Vol. 54, pp 11-29); such inhibitors alsoinclude tyrosine kinase inhibitors, for example inhibitors of theepidermal growth factor family (for example EGFR family tyrosine kinaseinhibitors such asN-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-amine(gefitinib, ZD1839),N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine(erlotinib, OSI-774) and6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)-quinazolin-4-amine(CI 1033), erbB2 tyrosine kinase inhibitors such as lapatinib,inhibitors of the hepatocyte growth factor family, inhibitors of theplatelet-derived growth factor family such as imatinib, inhibitors ofserine/threonine kinases (for example Ras/Raf signalling inhibitors suchas farnesyl transferase inhibitors, for example sorafenib (BAY43-9006)), inhibitors of cell signalling through MEK and/or AKT kinases,inhibitors of the hepatocyte growth factor family, c-kit inhibitors, ablkinase inhibitors, IGF receptor (insulin-like growth factor) kinaseinhibitors; aurora kinase inhibitors (for example AZD1152, PH739358,VX-680, MLN8054, R763, MP235, MP529, VX-528 AND AX39459) and cyclindependent kinase inhibitors such as CDK2 and/or CDK4 inhibitors;(v) antiangiogenic agents such as those which inhibit the effects ofvascular endothelial growth factor, [for example the anti-vascularendothelial cell growth factor antibody bevacizumab (Avastin™) and VEGFreceptor tyrosine kinase inhibitors such as4-(4-bromo-2-fluoroanilino)-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline(ZD6474; Example 2 within WO 01/32651),4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazoline(AZD2171; Example 240 within WO 00/47212), vatalanib (PTK787; WO98/35985) and SU11248 (sunitinib; WO 01/60814), compounds such as thosedisclosed in International Patent Applications WO97/22596, WO 97/30035,WO 97/32856 and WO 98/13354 and compounds that work by other mechanisms(for example linomide, inhibitors of integrin αvβ3 function andangiostatin)];(vi) vascular damaging agents such as Combretastatin A4 and compoundsdisclosed in International Patent Applications WO 99/02166, WO 00/40529,WO 00/41669, WO 01/92224, WO 02/04434 and WO 02/08213;(vii) antisense therapies, for example those which are directed to thetargets listed above, such as ISIS 2503, an anti-ras antisense;(viii) gene therapy approaches, including for example approaches toreplace aberrant genes such as aberrant p53 or aberrant BRCA1 or BRCA2,GDEPT (gene-directed enzyme pro-drug therapy) approaches such as thoseusing cytosine deaminase, thymidine kinase or a bacterial nitroreductaseenzyme and approaches to increase patient tolerance to chemotherapy orradiotherapy such as multi-drug resistance gene therapy; and(ix) immunotherapy approaches, including for example ex-vivo and in-vivoapproaches to increase the immunogenicity of patient tumour cells, suchas transfection with cytokines such as interleukin 2, interleukin 4 orgranulocyte-macrophage colony stimulating factor, approaches to decreaseT-cell anergy, approaches using transfected immune cells such ascytokine-transfected dendritic cells, approaches usingcytokine-transfected tumour cell lines and approaches usinganti-idiotypic antibodies.

Furthermore, for the treatment of the inflammatory diseases COPD, asthmaand allergic rhinitis the compounds of the invention may be combinedwith agents such as tumour necrosis factor alpha (TNF-alpha) inhibitorssuch as anti-TNF monoclonal antibodies (for example Remicade, CDP-870and adalimumab) and TNF receptor immunoglobulin molecules (such asEnbrel); non-selective cyclo-oxygenase COX-1/COX-2 inhibitors whetherapplied topically or systemically (such as piroxicam, diclofenac,propionic acids such as naproxen, flubiprofen, fenoprofen, ketoprofenand ibuprofen, fenamates such as mefenamic acid, indomethacin, sulindac,azapropazone, pyrazolones such as phenylbutazone, salicylates such asaspirin), COX-2 inhibitors (such as meloxicam, celecoxib, rofecoxib,valdecoxib, lumarocoxib, parecoxib and etoricoxib); glucocorticosteroids(whether administered by topical, oral, intramuscular, intravenous, orintra-articular routes); methotrexate, lefunomide; hydroxychloroquine,d-penicillamine, auranofin or other parenteral or oral goldpreparations.

The present invention still further relates to the combination of acompound of the invention and a leukotriene biosynthesis inhibitor,5-lipoxygenase (5-LO) inhibitor or 5-lipoxygenase activating protein(FLAP) antagonist such as; zileuton; ABT-761; fenleuton; tepoxalin;Abbott-79175; Abbott-85761; aN-(5-substituted)-thiophene-2-alkylsulfonamide;2,6-di-tert-butylphenolhydrazones; a methoxytetrahydropyrans such asZeneca ZD-2138; the compound SB-210661; a pyridinyl-substituted2-cyanonaphthalene compound such as L-739,010; a 2-cyanoquinolinecompound such as L-746,530; or an indole or quinoline compound such asMK-591, MK-886, and BAY×1005.

The present invention further relates to the combination of a compoundof the invention and a receptor antagonist for leukotrienes (LTB4, LTC4,LTD4, and LTE4) selected from the group consisting of thephenothiazin-3-1s such as L-651,392; amidino compounds such asCGS-25019c; benzoxalamines such as ontazolast; benzenecarboximidamidessuch as BIIL 284/260; and compounds such as zafirlukast, ablukast,montelukast, pranlukast, verlukast (MK-679), RG-12525, Ro-245913,iralukast (CGP 45715A), and BAY×7195.

The present invention still further relates to the combination of acompound of the invention and a phosphodiesterase (PDE) inhibitor suchas a methylxanthanine including theophylline and aminophylline; aselective PDE isoenzyme inhibitor including a PDE4 inhibitor aninhibitor of the isoform PDE4D, or an inhibitor of PDE5.

The present invention further relates to the combination of a compoundof the invention and a histamine type 1 receptor antagonist such ascetirizine, loratadine, desloratadine, fexofenadine, acrivastine,terfenadine, astemizole, azelastine, levocabastine, chlorpheniramine,promethazine, cyclizine, or mizolastine; applied orally, topically orparenterally.

The present invention still further relates to the combination of acompound of the invention and a gastroprotective histamine type 2receptor antagonist.

The present invention further relates to the combination of a compoundof the invention and an antagonist of the histamine type 4 receptor.

The present invention still further relates to the combination of acompound of the invention and an alpha-1/alpha-2 adrenoceptor agonistvasoconstrictor sympathomimetic agent, such as propylhexedrine,phenylephrine, phenylpropanolamine, ephedrine, pseudoephedrine,naphazoline hydrochloride, oxymetazoline hydrochloride, tetrahydrozolinehydrochloride, xylometazoline hydrochloride, tramazoline hydrochlorideor ethylnorepinephrine hydrochloride.

The present invention further relates to the combination of a compoundof the invention and an anticholinergic agent including muscarinicreceptor (M1, M2, and M3) antagonists such as atropine, hyoscine,glycopyrrrolate, ipratropium bromide, tiotropium bromide, oxitropiumbromide, pirenzepine or telenzepine.

The present invention still further relates to the combination of acompound of the invention together with a beta-adrenoceptor agonist(including beta receptor subtypes 1-4) such as isoprenaline, salbutamol,formoterol, salmeterol, terbutaline, orciprenaline, bitolterol mesylate,and pirbuterol.

The present invention further relates to the combination of a compoundof the invention and a chromone, such as sodium cromoglycate ornedocromil sodium.

The present invention still further relates to the combination of acompound of the invention together with an insulin-like growth factortype I (IGF-1) mimetic.

The present invention still further relates to the combination of acompound of the invention and a glucocorticoid, such as flunisolide,triamcinolone acetonide, beclomethasone dipropionate, budesonide,fluticasone propionate, ciclesonide or mometasone furoate.

The present invention still further relates to the combination of acompound of the invention together with an inhibitor of matrixmetalloproteases (MMPs), i.e., the stromelysins, the collagenases, andthe gelatinases, as well as aggrecanase; especially collagenase-1(MMP-1), collagenase-2 (MMP-8), collagenase-3 (MMP-13), stromelysin-1(MMP-3), stromelysin-2 (MMP-10), and stromelysin-3 (MMP-11) and MMP-9and MMP-12.

The present invention still further relates to the combination of acompound of the invention together with modulators of chemokine receptorfunction such as antagonists of CCR1, CCR2, CCR2A, CCR2B, CCR3, CCR4,CCR5, CCR6, CCR7, CCR8, CCR9, CCR10 and CCR11 (for the C—C family);CXCR1, CXCR2, CXCR3, CXCR4 and CXCR5 (for the C—X—C family) and CX3CR1for the C—X3-C family.

The present invention still further relates to the combination of acompound of the invention together with a cytokine or modulator ofcytokine function, including alpha-, beta-, and gamma-interferon;interleukins (IL) including IL1 to 15, and interleukin antagonists orinhibitors, including agents which act on cytokine signalling pathways.

The present invention still further relates to the combination of acompound of the invention together with an immunoglobulin (Ig) or Igpreparation or an antagonist or antibody modulating Ig function such asanti-IgE (omalizumab).

The present invention further relates to the combination of a compoundof the invention and another systemic or topically-appliedanti-inflammatory agent, such as thalidomide or a derivative thereof, aretinoid, dithranol or calcipotriol.

The present invention further relates to the combination of a compoundof the invention together with an antibacterial agent such as apenicillin derivative, a tetracycline, a macrolide, a beta-lactam, afluoroquinolone, metronidazole, an inhaled aminoglycoside; an antiviralagent including acyclovir, famciclovir, valaciclovir, ganciclovir,cidofovir, amantadine, rimantadine, ribavirin, zanamavir andoseltamavir; a protease inhibitor such as indinavir, nelfinavir,ritonavir, and saquinavir; a nucleoside reverse transcriptase inhibitorsuch as didanosine, lamivudine, stavudine, zalcitabine or zidovudine; ora non-nucleoside reverse transcriptase inhibitor such as nevirapine orefavirenz.

The present invention will now be further explained by reference to thefollowing illustrative examples in which the following abbreviations areused:

-   -   EtOAc ethyl acetate    -   DCM dichloromethane    -   NMP N-methylpyrrolidine    -   NBS N-bromosuccinimide    -   DMF N,N-dimethylformamide    -   DMSO dimethylsulfoxide    -   THF tetrahydrofuran    -   MeOH methanol    -   TFA trifluoroacetic acid    -   HCl hydrogen chloride    -   K₂CO₃ potassium carbonate    -   NaHCO₃ sodium hydrogen carbonate    -   Et₃N triethylamine    -   MeCN acetonitrile    -   rt room temperature    -   h hours    -   min minutes    -   M molar    -   MS mass spectrometry    -   PyBop Benzotriazol-1-yloxytripyrrolidinophosphonium        hexafluorophosphate    -   APCI atmospheric chemical ionisation method    -   ESI electron spray ionisation method    -   NMR nuclear magnetic resonance    -   HCl hydrochloric acid

Unless otherwise stated organic solutions were dried over magnesiumsulphate. RPHPLC denotes Reversed Phase Preparative High PerformanceLiquid Chromatography using Waters Symmetry C8, Xterra or PhenomenexGemini columns using acetonitrile and either aqueous ammonium acetate,ammonia, formic acid or trifluoroacetic acid as buffer whereappropriate. Column chromatography was carried out on silica gel.

EXAMPLE 1N-[3-(6-Amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl]-N-benzylacetamide

(i) 2-Chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine

2,6-Dichloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (55 g) was dissolvedin 7N-aqueous ammonia in methanol (500 ml) and heated at 100° C. in asealed flask for 6 h. The reaction mixture was cooled to rt and leftovernight. Filtration afforded the subtitle compound. Yield 40 g.

¹H NMR δ (CDCl₃) 8.02 (1H, s), 5.94 (2H, brs), 5.71 (1H, dd), 4.15-4.22(1H, m), 3.75-3.82 (1H, m), 1.27-2.12 (6H, m).

(ii) 2-Butoxy-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine

The product from step (i) (40 g) was dissolved in 19% (w/w)-sodiumbutoxide in butanol (250 ml). The reaction mixture was stirred underreflux for 6 h. The resultant suspension was cooled to rt, diluted withwater and extracted with diethyl ether. The combined organic phase waswashed with water, dried and concentrated in vacuo. The subtitlecompound was crystallized from diethyl ether/isohexane (1/1, 300 ml) andobtained by filtration. Yield 19 g.

¹H NMR δ (CDCl₃) 7.87 (1H, s), 5.56-5.68 (3H, m), 4.31-4.35 (2H, t),4.14-4.17 (1H, m), 3.76-3.80 (1H, m), 1.49-2.08 (10H, m), 0.98 (3H, t).

(iii) 8-Bromo-2-butoxy-9-(tetrahydro-2H-pyran-2-yl)9H-purin-6-amine

The product from step (ii) (30 g) was dissolved in dry DCM (200 ml). Thesolution was stirred at rt whilst N-bromosuccinimide (27 g) was addedportion wise. The mixture was stirred at rt overnight. 20% (w/v)-Sodiumsulfate (200 ml) was added and the separated aqueous phase extractedwith DCM. The combined organic phase was washed with saturated NaHCO₃solution and brine. After concentration in vacuo, the residue wasdissolved in EtOAc, washed with water, brine and dried. The solution wasfiltered through silica gel. The filtrate was concentrated in vacuo anddissolved in a mixture of diethyl ether and isohexane (1/1, 200 ml) togive the subtitle compound (26 g). The solvent was removed to give aresidue, which was purified by column chromatography (EtOAc/isohexane),which afforded 2.5 g. The solids were combined to give the subtitlecompound as a yellow solid. Yield 28.5 g. Melting point: 148-150° C.

¹H NMR δ (CDCl₃) 5.59-5.64 (3H, m), 4.32 (2H, m), 4.17 (1H, m), 3.74(1H, m), 3.08 (1H, m), 2.13 (1H, d), 1.48-1.83 (8H, m), 0.98 (3H, t).

(iv) 2-Butoxy-8-methoxy-9-(tetrahydro-2H-pyran-2-yl)9H-purin-6-amine

Sodium (3.7 g) was added to absolute methanol (400 ml) under a nitrogenatmosphere. To this solution was added the product (28.5 g) from step(iii) and the mixture was stirred at 65° C. for 9 h. The mixture wasconcentrated in vacuo and 500 ml of water added. The aqueous phase wasextracted with EtOAc and washed with brine and dried. The subtitlecompound was obtained after crystallisation from diethyl ether. Yield14.2 g.

¹H NMR δ (CDCl₃) 5.51 (1H, dd), 5.28 (2H, brs), 4.29 (2H, t), 4.11-4.14(4H, m), 3.70 (1H, m), 2.76-2.80 (1H, m), 2.05 (1H, d), 1.47-1.81 (8H,m), 0.97 (3H, t).

(v) 2-Butoxy-8-methoxy-9H-purin-6-amine, TFA salt

The product from step (iv) (24 g) was dissolved in absolute methanol(300 ml) and 30 ml of TFA was added. The reaction mixture was stirred atrt for 3 days and concentrated in vacuo. The subtitle compound wasobtained as a white crystalline solid after trituration withmethanol/EtOAc. Yield 21 g.

¹H NMR δ (CD₃OD), 4.48 (2H, t), 4.15 (3H, s), 1.80 (2H, quintet), 1.50(2H, sextet), 0.99 (3H, t).

(vi)2-[3-(6-Amino-2-butoxy-8-methoxy-9H-purin-9-yl)propyl]-1H-isoindole-1,3(2H)-dione

The product from step (v) (15 g) was dissolved in dry DMF (200 ml) and18 g of K₂CO₃ added. After the suspension was stirred at rt for 15 min,2-(3-bromopropyl)-1H-isoindole-1,3(211)-dione (14 g) was added thesuspension vigorously stirred at rt for 10 h. The reaction mixture wasextracted with EtOAc, washed with water and brine and dried. Thesubtitle compound was obtained after crystallisation from EtOAc/diethylether. Yield 16 g.

¹H NMR δ (DMSO-d₆) 7.83 (4H, m), 6.73 (2H, brs), 4.06 (2H, t), 4.01 (3H,s), 3.89 (2H, t), 3.58 (21-1, t), 2.07-2.14 (2H, m), 1.55-1.62 (2H, m),1.31-1.40 (2H, m), 0.90 (3H, t).

(vii) 9-(3-Aminopropyl)-2-butoxy-8-methoxy-9H-purin-6-amine

The product from step (vi) (1 g) was dissolved in ethanol (10 ml) andhydrazine monohydrate (1 ml) was added and stirred at ambienttemperature for 10 h. The resultant was concentrated under reducedpressure and the residue suspended in DCM (10 ml) and stirred for 1 h.The suspension was filtered, washed with DCM. The solution was washedwith water and dried. The solution was concentrated under reducedpressure to give the subtitled compound. Yield 700 mg.

¹H NMR δ (DMSO-d₆) 6.77 (21-1, brs), 4.16 (2H, t), 4.05 (3H, s), 3.89(2H, t), 2.46-2.52 (2H, m), 1.61-1.76 (4H, m), 1.35-1.45 (2H, m), 0.92(31-1, t).

(viii)6-Amino-9-[3-(benzylamino)propyl]-2-butoxy-7,9-dihydro-8H-purin-8-one,dihydrochloride

The product from step (vii) (4 g) and benzaldehyde (1.6 g) weredissolved in THF (40 ml) and stirred at rt for 24 h. Sodium borohydride(0.8 g) and 5 drops of methanol was added and stirred at a rt overnight.The solvent was evaporated under reduced pressure and the residuepartitioned between EtOAc and brine. The organic layer was separated,washed with water, dried and evaporated under reduced pressure. Theresidue was dissolved in MeOH (100 ml), conc. HCl (10 ml) added andstirred at rt for 72 h. The solvent was evaporated under reducedpressure and the residue triturated with MeOH/EtOAc. Yield 3.64 g.

¹H NMR δ (DMSO-d₆) 10.96 (1H, s); 9.23 (2H, brs); 7.53-7.38 (5H, m);4.26 (2H, t); 4.11 (2H, t); 3.78 (2H, t); 2.93-2.91 (2H, m); 2.10-2.03(2H, m); 1.71-1.64 (2H, m); 1.46-1.36 (2H, m); 0.93 (3H, t).

MS: APCI (+ve): 371.

(ix)N-[3-(6-Amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl]-N-benzylacetamide

Acetylchloride (0.08 ml) was added to a mixture of the product from step(viii) (250 mg) and triethylamine (0.6 ml) in NMP (5 ml) and stirred for2 h. The mixture was purified by to RPHPLC, yield 85 mg.

¹H NMR δ (DMSO-d₆) rotomers present 9.86 and 9.82 (1H, 2×s); 7.35-7.10(5H, m); 6.41 and 6.39 (2H, 2×s); 4.56 and 4.46 (2H, 2×s); 4.14-4.10(2H, m); 3.68-3.60 (2H, m); 3.25-3.18 (2H, m); 2.01 and 1.99 (3H, 2×s);1.95-1.80 (2H, m); 1.65-1.60 (2H, m); 1.41-1.35 (2H, m); 0.91 (3H, t).

MS: APCI (+ve): 413.

EXAMPLE 2N-[3-(6-Amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl]-N-benzyl-2-methoxyacetamide

The title compound was prepared by the method of example 1 usingmethoxyacetyl chloride.

¹H NMR δ (DMSO-d₆) rotomers present 9.87 (1H, s); 7.34-7.11 (5H, m);6.42 and 6.40 (2H, 2×s); 4.51 and 4.48 (2H, 2×s); 4.14 and 4.11 (2H, m);4.07 and 4.05 (2H, 2×s); 3.67-3.60 (2H, m); 3.26-3.13 (5H, m); 1.96-1.81(2H, m); 1.66-1.59 (2H, m); 1.42-1.33 (2H, m); 0.91 (3H, t).

MS: APCI (+ve): 443.

EXAMPLE 3 Methyl4-[[3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl](benzyl)amino]-4-oxobutanoate

PyBop (0.47 g) was added to a mixture of the product from example 1 step(viii) (0.25 g), Et₃N (0.7 ml) and succinic acid monomethyl ester (0.16g) in DMF (8 ml) and stirred at rt for 4 days. MeOH (10 ml) was added,the solvent evaporated under reduced pressure and the residue purifiedby RPHPLC, yield 46 mg.

¹H NMR δ (DMSO-d₆) rotomers present 9.86 and 9.82 (1H, 2×s); 7.34-7.09(5H, m); 6.41 and 6.39 (2H, 2×s); 4.60 and 4.47 (2H, 2×s); 4.14-4.10(2H, m); 3.70-3.58 (2H, m); 3.57 to and 3.56 (3H, 2×s); 3.26-3.21 (2H,m); 2.60-2.57 (2H, m); 1.98-1.78 (2H, m); 1.65-1.60 (2H, m); 1.40-1.34(2H, m); 0.91 (3H, t).

MS: APCI (+ve): 485.

Examples 4-10 were prepared by the same method as Example 3.

EXAMPLE 4N-[3-(6-Amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl]-N-benzyl-3-methoxypropanamide

¹H NMR δ (DMSO-d₆) rotomers present 9.86 and 9.82 (1H, 2×s); 7.33-7.10(5H, m); 6.41 and 6.39 (2H, 2×s); 4.58 and 4.48 (2H, 2×s); 4.12 (2H, t);3.68-3.50 (4H, m); 3.25-3.23 (2H, m); 3.20 and 3.17 (3H, 2×s); 1.96-1.78(2H, m); 1.67-1.58 (2H, m); 1.40-1.35 (2H, m); 0.91 (3H, t).

MS: APCI (+ve): 457.

EXAMPLE 5N-[3-(6-Amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl]-N-benzyl-N′,N′-dimethylsuccinamide

¹H NMR δ (DMSO-d₆) rotomers present 9.85 (1H, s); 7.35-7.10 (5H, m);6.41 and 6.39 (2H, 2×s); 4.60 and 4.47 (2H, 2×s); 4.13-4.10 (2H, m);3.69-3.60 (2H, m); 3.27-3.20 (2H, m); 2.97 and 2.95 (3H, 2×s); 2.80 and2.79 (3H, 2×s); 2.54 (2H, s); 1.98-1.79 (2H, m); 1.64-1.59 (2H, m);1.40-1.35 (2H, m); 0.91 (3H, t).

MS: APCI (+ve): 498.

EXAMPLE 6N-[3-(6-Amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl]-N-benzyl-2-[4-(methylsulfonyl)phenyl]acetamide

¹H NMR δ (DMSO-d₆) rotomers present 9.89 and 9.82 (1H, 2×s); 7.84-7.81(2H, m); 7.44-7.11 (7H, m); 6.44-6.39 (2H, 2×s); 4.66 and 4.50 (2H,2×s); 4.13-4.08 (2H, m); 3.84 (2H, s); 3.70-3.60 (2H, m); 3.29-3.26 (2H,m); 3.20 and 3.18 (3H, 2×s); 2.01-1.80 (2H, m); 1.66-1.56 (2H, m);1.41-1.29 (2H, m); 0.92-0.86 (3H, m).

MS: APCI (+ve): 567.

EXAMPLE 7N-[3-(6-Amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl]-N-benzyl-2-(4-benzylpiperazin-1-yl)acetamide

¹H NMR δ (DMSO-d₆) rotomers present 9.86 and 9.81 (1H, 2×s); 7.33-7.12(10H, m); 6.41 and 6.39 (2H, 2×s); 4.66 and 4.48 (2H, 2×s); 4.15-4.09(2H, m); 3.69-3.56 (2H, m); 3.41 and 3.35 (2H, 2×s); 3.32-3.14 (2H, m);3.11 and 3.01 (2H, 2×s); 2.43-2.18 (8H, m); 2.02-1.75 (2H, m); 1.66-1.58(2H, m); 1.41-1.31 (2H, m); 0.93-0.87 (3H, m).

MS: APCI (+ve): 587.

EXAMPLE 8N-[3-(6-Amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl]-N-benzyl-2-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)acetamide

¹H NMR δ (DMSO-d₆) rotomers present 9.86 (1H, brs); 7.39-7.12 (5H, m);6.42 and 6.39 (2H, 2×s); 5.12 and 5.03 (2H, 2×s); 4.66 and 4.49 (2H,2×s); 4.11 (2H, t); 3.73-3.61 (2H, m); 3.28-3.24 (2H, m); 2.24 and 2.20(3H, 2×s); 2.15 and 2.12 (3H, 2×s); 2.06-1.80 (2H, m); 1.64-1.57 (2H,m); 1.40-1.33 (2H, m); 0.93-0.88 (3H, m).

MS: APCI (+ve): 508.

EXAMPLE 9N-[3-(6-Amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl]-N-benzyl-3-pyrazin-2-ylpropanamide

¹H NMR δ (DMSO-d₆) rotomers present 9.84 and 9.82 (1H, 2×s); 8.55 (1H,d); 8.50 (1H, d); 8.43 (1H, dd); 7.32-7.04 (5H, m); 6.40 (2H, s); 4.61and 4.46 (2H, 2×s); 4.13-4.08 (2H, m); 3.70-3.57 (2H, m); 3.29-3.21 (2H,m); 3.04-3.00 (2H, m); 2.83-2.79 (2H, m); 1.97-1.78 (2H, m); 1.64-1.58(2H, m); 1.38-1.34 (2H, m); 0.92-0.87 (3H, m).

MS: APCI (+ve): 505.

EXAMPLE 10N-[3-(6-Amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl]-N-benzyl-N³,N³-dimethyl-β-alaninamide

¹H NMR δ (DMSO-d₆) rotomers present 9.87 and 9.82 (1H, 2×s); 7.36-7.10(5H, m); 6.41 and 6.39 (2H, 2×s); 4.59 and 4.47 (2H, 2×s); 4.12 (2H, t);3.69-3.60 (2H, m); 3.28-3.18 (2H, m); 2.46-2.32 (4H, m); 2.06-2.04 (6H,2×s); 1.96-1.80 (2H, m); 1.65-1.59 (2H, m); 1.41-1.34 (2H, m); 0.93-0.88(3H, m).

MS: APCI (+ve): 470.

Biological Assay Human TLR7 Assay

Recombinant human TLR7 was stably expressed in a HEK293 cell linealready stably expressing the pNiFty2-SEAP reporter plasmid; integrationof the reporter gene was maintained by selection with the antibioticzeocin. The most common variant sequence of human TLR7 (represented bythe EMBL sequence AF240467) was cloned into the mammalian cellexpression vector pUNO and transfected into this reporter cell-line.Transfectants with stable expression were selected using the antibioticblasticidin. In this reporter cell-line, expression of secreted alkalinephosphatase (SEAP) is controlled by an NFkB/ELAM-1 composite promotercomprising five NFkB sites combined with the proximal ELAM-1 promoter.TLR signaling leads to the translocation of NFkB and activation of thepromoter results in expression of the SEAP gene. TLR7-specificactivation was assessed by determining the level of SEAP producedfollowing overnight incubation of the cells at 37° C. with the standardcompound in the presence of 0.1% (v/v) dimethylsulfoxide (DMSO).Concentration dependent induction of SEAP production by compounds wasexpressed as the concentration of compound which produced half of themaximal level of SEAP induction for that compound (pEC50). The resultsobtained are shown in Table 1 following.

TABLE 1 Compound of Example No. pEC50 1 7.2 2 7.3 3 7.4 4 7.1 5 7.1 67.1 7 8.1 8 6.8 9 7.3 10 7.5

1. A compound of formula

wherein R¹ represents hydrogen, hydroxyl, or a C₁-C₆ alkoxy, C₂-C₅alkoxycarbonyl, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, C₆-C₁₀ aryl, C₅-C₁₀heteroaryl or C₃-C₈ cycloalkyl group, each group being optionallysubstituted by one or more substituents independently selected fromhalogen, hydroxyl, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆haloalkoxy, C₂-C₅ alkoxycarbonyl, amino, (mono)-C₁-C₆ alkylamino and(di)-C₁-C₆ alkylamino; Y¹ represents a single bond or C₁-C₆ alkylene; X¹represents a single bond, an oxygen or sulphur atom, sulphonyl or NR³;Z¹ represents a C₂-C₆ alkylene or C₃-C₈ cycloalkylene group, each groupbeing optionally substituted by at least one hydroxyl; X² representsNR⁴; Y² represents a single bond or C₁-C₆ alkylene; n is an integer 0, 1or 2; each R² group independently represents halogen, cyano, S(O)_(m)R⁹,OR¹⁰, SO₂NR¹⁰R¹¹, CONR¹⁰R¹¹, NR¹⁰R¹¹, NR¹⁰SO₂R⁹, NR¹⁰CO₂R⁹, NR¹⁰COR⁹,C₆-C₁₀ aryl, C₅-C₁₀ heteroaryl, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl or C₃-C₈ cycloalkyl, the latter six groups being optionallysubstituted by one or more substituents independently selected fromhalogen, cyano, S(O)_(p)R¹², OR¹³, SO₂NR¹³R¹⁴, CONR¹³R¹⁴, NR¹³R¹⁴,NR¹³SO₂R¹², NR¹³CO₂R¹², NR¹³COR¹², C₁-C₆ alkyl, C₁-C₃ haloalkyl andC₃-C₈ cycloalkyl; R³ represents hydrogen or C₁-C₆ alkyl; R⁴ representsCO₂R⁵, SO₂R⁵, COR⁵, SO₂NR⁶R⁷ or CONR⁶R⁷; R⁵ represents (i) a 3- to8-membered saturated heterocyclic ring containing 1 or 2 ringheterogroups independently selected from NR⁸, S(O)_(q) or oxygen, thering being optionally substituted by one or more substituentsindependently selected from halogen, hydroxyl, C₁-C₆ alkyl and C₁-C₆alkoxy, or (ii) a C₆-C₁₀ aryl or C₅-C₁₀ heteroaryl group, each of whichmay be optionally substituted by one or more substituents independentlyselected from halogen, cyano, C₁-C₆ alkyl, C₁-C₃ haloalkyl, S(O)_(r)R⁹,OR¹⁰, CO₂R¹⁰, SO₂NR¹⁰R¹¹, CONR¹⁰R¹¹, NR¹⁰R¹¹, NR¹⁰SO₂R⁹, NR¹⁰CO₂R⁹ andNR¹⁰COR⁹, or (iii) a C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl or C₃-C₈cycloalkyl group, each of which may be optionally substituted by one ormore substituents independently selected from halogen, cyano, C₃-C₈cycloalkyl, S(O)_(t)R¹², OR¹³, COR¹³, CO₂R¹³, SO₂NR¹³R¹⁴, CONR¹³R¹⁴,NR⁶R⁷, NR¹³SO₂R¹², NR¹³CO₂R¹², NR¹³COR¹², C₆-C₁₀ aryl and C₅-C₁₀heteroaryl, the latter two substituents themselves being optionallysubstituted by one or more substituents independently selected fromC₁-C₆ alkyl, halogen, hydroxy, methylsulphonyl and cyano; R⁶ representsa hydrogen atom or a group selected from C₁-C₆ alkyl, C₂-C₆ alkenyl,C₂-C₆ alkynyl, C₃-C₈ cycloalkyl group and a heterocyclic moiety, whichgroup may be optionally substituted by one or more substituentsindependently selected from halogen, hydroxyl, oxo, cyano, C₁-C₆ alkyl,C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₈ cycloalkyl, OR¹⁵, S(O)_(v)R¹⁵,CO₂R¹⁶, COR¹⁶, NR¹⁶R¹⁷, CONR¹⁶R¹⁷, NR¹⁶COR¹⁷, NR¹⁶CO₂R¹⁵, SO₂NR¹⁶R¹⁷,NR¹⁶SO₂R¹⁵, C₆-C₁₀ aryl, C₅-C₁₀ heteroaryl and a heterocyclic moiety,the latter three substituents themselves being optionally substituted byone or more substituents independently selected from C₁-C₆ alkyl, C₃-C₈cycloalkyl, halogen, S(O)_(w)R¹⁵, CO₂R¹⁶, COR¹⁶, hydroxy and cyano, andR⁷ represents a hydrogen atom or a C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl or C₃-C₈ cycloalkyl group, each group being optionallysubstituted by one or more substituents independently selected fromhalogen, C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, C₅-C₁₀ heteroaryl, carboxy,cyano, OR¹⁵, hydroxy and NR¹⁸R¹⁹, or R⁶ and R⁷ together with thenitrogen atom to which they are attached form a 3- to 8-memberedsaturated or partially saturated heterocyclic ring optionally containinga further ring heterogroup selected from nitrogen, S(O)_(x) and oxygen,the heterocyclic ring being optionally substituted by one or moresubstituents independently selected from halogen, hydroxyl, carboxyl,cyano, OR²⁰, NR²¹R²², S(O)_(y)R²³, COR²⁴, CO₂R²⁴, NR²⁴R²⁵, CONR²⁴R²⁵,NR²⁴COR²⁵, NR²⁴CO₂R²³, SO₂NR²⁴R²⁵, NR²⁴SO₂R²³, C₆-C₁₀ aryl, benzyl,C₅-C₁₀ heteroaryl, a heterocyclic moiety, C₁-C₆ alkyl, C₂-C₆ alkenyl,C₂-C₆ alkynyl and C₃-C₈ cycloalkyl, the latter eight substituentsthemselves being optionally substituted by one or more substituentsindependently selected from halogen, oxo, cyano, OR²¹, S(O)_(z)R²³,COR²⁴, CO₂R²⁴ and NR²⁴R²⁵; each R⁸, R¹⁰, R¹¹, R¹³, R¹⁴, R¹⁶, R¹⁷, R¹⁸,R¹⁹, R²¹, R²², R²⁴ and R²⁵ independently represents a hydrogen atom or aC₁-C₆ alkyl or C₃-C₆ cycloalkyl group; each R⁹, R¹², R¹⁵ and R²³independently represents C₁-C₆ alkyl or C₃-C₆ cycloalkyl; R²⁰ representsa C₁-C₆ alkyl group optionally substituted by one or more substituentsindependently selected from halogen, hydroxyl and OR²³; m, p, q, r, t,v, w, x, y and z each independently represent an integer 0, 1 or 2; andA represents a C₆-C₁₀ aryl or C₅-C₁₂ heteroaryl group; or apharmaceutically acceptable salt thereof.
 2. A compound according toclaim 1, wherein R¹ represents hydrogen.
 3. A compound according toclaim 1, wherein Y¹ represents C₁-C₆ alkylene.
 4. A compound accordingto claim 1, wherein X¹ represents an oxygen atom.
 5. A compoundaccording to claim 1, wherein Z¹ represents C₂-C₆ alkylene.
 6. Acompound according to claim 1, wherein X² represents NR⁴ and R⁴represents COR⁵.
 7. A compound according to claim 1, wherein R⁵represents C₁-C₄ alkyl optionally substituted by one or two substituentsindependently selected from fluorine, chlorine, cyano, C₃-C₆ cycloalkyl,S(O)_(t)R¹², OR¹³, COR¹³, CO₂R¹³, SO₂NR¹³R¹⁴, CONR¹³R¹⁴, NR⁶R⁷,NR¹³SO₂R¹², NR¹³CO₂R¹², NR¹³COR¹², phenyl and C₅-C₆ heteroaryl, thelatter two substituents themselves being optionally substituted by one,two, three or four substituents independently selected from C₁-C₄ alkyl,fluorine, chlorine, hydroxy, methylsulphonyl and cyano.
 8. A compoundaccording to claim 1, wherein Y² represents C₁-C₆ alkylene.
 9. Acompound according to claim 1, wherein A represents C₆-C₁₀ aryl.
 10. Acompound according to claim 1 being:N-[3-(6-Amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl]-N-benzylacetamide,N-[3-(6-Amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl]-N-benzyl-2-methoxyacetamide,Methyl4-[[3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl](benzyl)amino]-4-oxobutanoate,N-[3-(6-Amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl]-N-benzyl-3-methoxypropanamide,N-[3-(6-Amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl]-N-benzyl-N′,N′-dimethylsuccinamide,N-[3-(6-Amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl]-N-benzyl-2-[4-(methylsulfonyl)phenyl]acetamide,N-[3-(6-Amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl]-N-benzyl-2-(4-benzylpiperazin-1-yl)acetamide,N-[3-(6-Amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl]-N-benzyl-2-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)acetamide,N-[3-(6-Amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl]-N-benzyl-3-pyrazin-2-ylpropanamide,orN-[3-(6-Amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl]-N-benzyl-N³,N³-dimethyl-β-alaninamide,or a pharmaceutically acceptable salt of any one thereof.
 11. A processfor the preparation of a compound of formula (I) or a pharmaceuticallyacceptable salt thereof as claimed in claim 1 which comprises, (a) whenR⁴ represents a group COR⁵, reacting a compound of formula

wherein n, R¹, R², A, X¹, Y¹, Z¹ and Y² are as defined in claim 1, witha compound of formula (III), R⁵—C(O)-L¹, wherein L¹ represents halogenor hydroxy and R⁵ is as defined in claim 1, in the presence of a base ora coupling reagent as required; (b) when R⁴ represents a group COR⁵ andR⁵ represents a group C₁-C₆ alkyl-NR⁶R⁷, reacting a compound of formula

wherein R³⁰ represents a C₁-C₆ alkyl group, L² represents a leavinggroup and n, R¹, R², A, X¹, Y¹, Z¹ and Y² are as defined in claim 1,with a compound of formula (V), NHR⁶R⁷, wherein R⁶ and R⁷ are as definedin claim 1, in the presence of a base; (c) when R⁴ represents a groupSO₂R⁵, reacting a compound of formula (II) as defined in (a) above witha compound of formula (VI), L³-S(O)₂—R⁵, wherein L³ represents a leavinggroup and R⁵ is as defined in claim 1, in the presence of a base; (d)when R⁴ represents a group CO₂R⁵, reacting a compound of formula (II) asdefined in (a) above with a compound of formula (VII), L⁴-C(O)—OR⁵,wherein L⁴ represents a leaving group and R⁵ is as defined in claim 1,in the presence of a base; (e) when R⁴ represents a group SO₂NR⁶R⁷,reacting a compound of formula (II) as defined in (a) above with acompound of formula (VIII), L⁵-S(O)₂—NR⁶R⁷, wherein L⁵ represents aleaving group and R⁶ and R⁷ are as defined in claim 1, in the presenceof a base; or (f) when R⁴ represents a group CONR⁶R⁷, reacting acompound of formula (II) as defined in (a) above with a compound offormula (IX), L⁶-C(O)—NR⁶R⁷, wherein L⁶ represents a leaving group andR⁶ and R⁷ are as defined in claim 1, in the presence of a base; andoptionally thereafter carrying out one or more of the followingprocedures: converting a compound of formula (I) into another compoundof formula (I), removing any protecting groups, forming apharmaceutically acceptable salt.
 12. A pharmaceutical compositioncomprising a compound of formula (I) or a pharmaceutically acceptablesalt thereof as claimed in claim 1 or claim 10 in association with apharmaceutically acceptable adjuvant, diluent or carrier.
 13. (canceled)14. A method of treating asthma, COPD, allergic rhinitis, allergicconjunctivitis, atopic dermatitis, cancer, hepatitis B, hepatitis C,HIV, HPV, bacterial infections or dermatosis which comprisesadministering to a patient in need thereof a therapeutically effectiveamount of a compound of formula (I) or a pharmaceutically acceptablesalt thereof as claimed in claim
 1. 15. A method of treating, orreducing the risk of, an allergic or viral disease or cancer whichcomprises administering to a patient in need thereof a therapeuticallyeffective amount of a compound of formula (I) or a pharmaceuticallyacceptable salt thereof as claimed in claim 1.